PROJECT SUMMARY Approximately 24,000 new cases of thoraco-abdominal aortic aneurysms (TAAAs) are diagnosed each year in the USA. The most feared complication of TAAA open repair is paraplegia (5-10% of patients) caused by ischemic spinal cord (SC) injury following surgery. Therefore, there is urgency to identify new molecules that would complement existent, non-pharmacological preventive strategies. With this aim, we developed a mouse and a dog model of TAAA open repair where aortic cross-clamping (ACC) results in central cord edema, gray matter damage, and hindlimb paralysis. MicroRNAs are short, non-coding RNAs that negatively regulate the expression of multiple target genes and have been implicated in a number of pathologies. We have shown that miR-155, a microRNA established by us and others to be highly pro-inflammatory, is causal in inducing exacerbated inflammation that leads to blood-SC barrier leakage, central cord edema development, gray matter damage, and paralysis. Namely, we found that mice with miR-155 global deletion present a rate of paralysis 62.5% of that of wild-type mice, associated with reduced gray matter damage. In addition, we found that, under ischemic conditions, miR-155 impairs the expression of Mfsd2a (Major facilitator superfamily domain containing 2a), a gene that encodes an endothelial transporter of omega-3 docosahexaenoic acid (DHA, 22:6n-3) that is also implicated in the maintenance of the integrity of the blood- brain barrier. Importantly, the brain, whose phospholipids contain 15% of DHA, however cannot synthesize this compound and therefore needs a constant supply of it. DHA is key for both the function of the brain and the production of powerful anti-inflammatory derivatives (docosanoids and elovanoids) that are critical to brain homeostasis. Accordingly, we found that the SC of non-paralyzed mice express Mfsd2a levels significantly higher than paralyzed mice after ACC. Therefore, we propose two independent approaches to reduce the rate of paralysis following ischemia: (1) Directly blocking miR-155 deleterious activity using a miR-155 antisense oligonucleotide; and (2) Increasing DHA supply to the SC. Both treatments will impair the development of local and systemic inflammation, reduce the development of central cord edema and gray matter damage, and consequently decrease the rate of paralysis. While miR-155 and DHA effects has been previously studied in stroke models, thus providing strong ground for our strategies, they were never tested in our mouse ACC model. As TAAA repair follows a programmed surgical procedure, providing a window of opportunity for preventive intervention, our strategies hold a strong translational potential in TAAA open repair surgery. In the future, they could also be tested in our canine and mouse models (under development) of endovascular aortic repair.